A central theme of the program project is the use of allogeneic blood progenitor cell transplantation to induce host versus donor and donor versus host immune tolerance in patients and laboratory animals after the development of chimerism without the development of graft versus host disease (GVHD). The role of regulatory T cells in the protection against GVHD will be studied as well as the immune competence of the protected hosts. We will test the hypothesis that sustained chimerism achieved with a novel conditioning regimen will induce immune tolerance in patients given kidney transplants such that all immune suppressive drugs can be withdrawn. We will also test the hypothesis that regulatory natural killer T cells in the blood of these patients will suppress immune responses to donor and host alloantigens. We will use a conditioning regimen to induce full chimerism in patients with life threatening systemic lupus erythematosus who will be protected against GVHD by regulatory T cells. We will test the hypothesis that sustained chimerism will induce a complete remission in the autoimmune disease allowing for immunosuppressive drug withdrawal. We will test the hypothesis that regulatory T cells (CD4+CD25+or NK1.1+ T cells) can separate GVHD from graft versus tumor/lymphoma (GVL) activity in mice by blocking different immune effector pathways such that potent GVL activity occurs in the absence of GVHD. We will test the hypothesis that donor Langerhans cell replacement of host Langerhans cells in the skin after allogeneic bone marrow transplantation is dependent on the function of donor T cells that facilitate replacement even in the absence of clinical or microscopic GVHD. We will also study Langerhans cell replacement in chimeric kidney transplant and autoimmune disease patients, and Langerhans cell replacement in mice protected from GVHD with regulatory T cells. The administrative and biostatistical core will serve the needs of all projects, and the immune assay and flow cytometry core will service all projects as well.
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